Chronic Obstructive Pulmonary Disease (COPD) that comprises emphysema and chronic bronchitis, is a major public health burden that afflicts >800 million people worldwide and will become the third leading cause of death by 2020. Cigarette smoking represents the major risk factor for COPD. Cigarette smoking causes chronic oxidative stress that induces- oxidative damage to biomolecules resulting in alveolar epithelial injury and apoptosis, oxidative inactivation of antiproteases (11-antitrypsin) and surfactants resulting in remodeling of extracellular matrix, inactivation of histone deacytelase-2 (HDAC2) that promotes inflammation and causes corticosteroid resistance and mucus hypersecretion resulting in bronchitis. However, it is unclear (1) if increased oxidative stress and inflammation in lungs of COPD patients is a result of suboptimal antioxidant enzyme expression and whether suboptimal expression of antioxidant defenses are associated with the severity of COPD. Our preclinical studies have demonstrated Nrf2 as master regulator of a network of cytoprotective genes that includes antioxidant defenses in response to cigarette smoke and collectively protect against oxidative damage to macromolecules and attenuate inflammation and lung tissue injury. In response to chronic cigarette smoke exposure, Nrf2-disrupted mice lungs develops early and sever emphysema that is mainly mediated by impaired antioxidant defenses, oxidative damage, apoptosis and inflammation. However the regulatory role of Nrf2 pathway in human COPD pathogenesis is not clear. We hypothesize that there is a significant and progressive decline in the NRF2 activity leading to decreased expression of its lung antioxidant transcriptional targets in COPD lungs when compared to non-COPD lungs. This is an exploratory research proposal with main objective of investigating status Nrf2 pathway and oxidative damage with severity of COPD in limited number of lung tissue samples procured from LTRC. The proposal will measure expression of Nrf2, its co-regulators, antioxidant defenses, oxidative damage in lung samples from non-COPD smokers, mild COPD smokers and sever COPD smokers. These studies will decipher the role of Nrf2 in COPD pathogenesis and may suggest a novel molecular target for drug development. (End of Abstract) PUBLIC HEALTH RELEVANCE: Public Health Relevance Statement COPD major public health burden that afflicts >800 million people worldwide and will become the third leading cause of death by 2020. Current therapies (corticosteroid and bronchodilators) treat the symptoms but faila to stop or reverse the disease progression. Therefore, there is an urgent need of new molecular targets for development of therapies. This application focuses on deciphering the regulatory role of Nrf2 in the pathogenesis of COPD. Positive results will help in development of therapies targeting Nrf2 pathway.